Nearly one-third of the U.S. population is overweight, contributing to atherosclerosis, hypertension and diabetes, and accounting for a majority of deaths in Western populations and an estimated 5 percent of total U.S. health care costs. Obesity is a complex trait that is influenced by environmental and genetic factors and their interactions. Obesity clearly has a polygenic basis or predisposition. Due to the complexities and low power inherent in quantitative trait loci (QTL) identification studies in humans, there have recently been major efforts to genetically dissect obesity and its correlated effects in a variety of animal models. Despite their potential significance, genes controlling energy requirements and expenditure through metabolic rate (MR) have not received sufficient emphasis. Highly unique populations of mice have been established at the University of Nebraska that have undergone long-term divergent selection for MR measured as heat loss (followed by full-sib mating to create inbred lines), as a model for study of the polygenic control of energy balance and body composition. These lines (MH=high MR; ML=low MR) exhibit extreme phenotypic divergence for these target traits and are genetically predisposed to high and low energy expenditure. The genetic differences between the lines are recalcitrant to factors such as gender, age and diet. A large F2 population will be made from crosses between MH and ML. The F2 population will be phenotyped for MR (by direct calorimetry), feed intake and body composition, and genotyped at approximately 160 microsatellite markers throughout the genome. Locations of QTL controlling MR, maintenance energy requirements and fat percentage will be identified. QTL with largest effects will be fine-mapped using targeted dense genotyping in an advanced intercross line created by intermating MH and ML to F10. The long-term goal of this research is to understand the complex nature of the polygenic control of obesity in humans through analysis of loci predisposing mice to high or low metabolic rate and maintenance requirements. QTL identified in mice likely have homologs in humans with important effects on energy balance and fat deposition. This research may lead to eventual identification of these loci through candidate positional cloning. These efforts will contribute to the long-term battle against human obesity by facilitating improved methods for diagnosis, treatment and prevention.